Benzenesulfonyl ureas having hypoglycemic activity

ABSTRACT

BENZENESULFONYL UREA COMPOUNDS THAT ARE EFFECTIVE AS ORAL ANTIDIABETIC AGENTS ARE DISCLOSED TO HAVE THE FORMULA   1-(X-N(-X1)-CO-NH-Y-),4-(R-HN-CO-HN-O2S-)BENZENE   WHEREIN   R IS (A) ALKYL OR ALKENYL OF 3-6 CARBON ATOMS, (B) ENDOALKYLENE-CYCLOHEXYL, ENDOALKYLENE-CYCLOHEXENYL, ENDOALKYLENE-CYCLOHEXYLMETHYL OR ENDOALYLENE-CYCLOHEXENYLMETHYL OF 1-2 ENDOALKYLENE CARBON ATOMS, (C) BENZYL, PHENYLETHYL, (D) CYCLOHEXYL METHY, (E) LOWER ALKYL CYCLOHEXYL OR DIALKYL CYCLOHEXYL METHYL CYCLOPENTYL, (F) CYCLOALKYL OF 5-8 CARBON ATOMS IN THE RING (G) CYCLOHEXENYL, CYCLOHEXENYL-METHYL, METHYLCYCLOHEXENYL OR (H) NORTRICYCLYL, X IS (A) PHENYL, TRIFLUOROMETHYL PHENYL SUBSTITUTED BY ONE TO TWO SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HALOGEN, LOWER ALKYL AND LOWER ALKOXY OR (B) BENZYL, X1 IS ALKYL OF 1 TO 3 CARBON ATOMS, AND Y IS A SATURATED HYDROCARBON OF 1 TO 3 CARBON ATOMS.

United States Patent 01 lice 3,655,756 Patented Apr. 11, 1972 Int. c1.127/00 US. Cl. 260553 D 16 Claims ABSTRACT OF THE DISCLOSUREBenzenesulfonyl urea compounds that are effective as oral antidiabeticagents are disclosed to have the formula wherein R is (a) alkyl oralkenyl of 3-6 carbon atoms,

(b) endoalkylene-cyclohexyl, endoalkylene cyclohexenyl,endoalkylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl of 1-2endoalkylene carbon atoms,

(c) benzyl, phenylethyl,

(d) cyclohexyl methyl,

(e) lower alkyl cyclohexyl or dialkyl cyclohexyl methyl cyclopentyl,

(f) cycloalkyl of 5-8 carbon atoms in the ring (g) cyclohexenyl,cyclohexenyl-methyl, methylcyclohexenyl, or

(h) nortricyclyl,

X is

(a) phenyl, trifluoromethyl phenyl, phenyl substituted by one to twosubstituents selected from the group consisting of halogen, lower alkyland lower alkoxy, or

(b) benzyl,

X is alkyl of 1 to 3 carbon atoms, and Y is a saturated hydrocarbon of 1to 3 carbon atoms.

This application is a continuation-in-part of our copending applicationSer. No. 511,990 filed on Dec. 6, 1965, and Ser. No. 636,290 filed May5, 1967, both of which are now abandoned.

The present invention provides benzenesulfonyl-ureas corresponding tothe general formula NCNY s oi-NH-o O-NH-R X{ t as well as salts of saidbenzenesulfonyl-ureas. In the formula R stands for:

(a) alkyl or alkenyl of 3 to 6 carbon atoms,

(b) benzyl, phenylethyl,

(c) cyclohexylmethyl,

(d) endoalikylene-cyclohexyl, endoalkylene cyclohexenyl,endoalkylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl of 1-2endoalkylene carbon atoms,

(e) lower alkylcyclohexyl, lower dialkylcyclohexyl,

methyl cyclopentyl,

(f) 'cycloalkyl of 5 to 8 carbon atoms,

(g) cyclohexenyl, cyclohexenyl methyl, methyl cyclohexenyl, (h)nortricyclyl, t a Y represents a saturated hydrocarbon chain containing1-3 carbon atoms, X is a (a) phenyl, trifluoromethyl phenyl,nitrophenyl, methylenedioxyphenyl, phenyl substituted by one to twosubstituents selected from the group consisting of halogen, lower alkyland lower alkoxy, or (b) benzyl and X is alkyl of 1 to 3 carbon atoms.

In the foregoing and the following definitions lower alkyl in every casestands for an alkyl group containing 1-4 carbon atoms in straight orramified chain.

According to the above-mentioned definitions R may represent, forinstance, propyl, isopropyl, butyl, isobutyl, sec. butyl,straight-chained or ramified amyl (pentyl) or hexyl as well as theradicals corresponding to said hydrocarbon radicals and containing anethylenic double linkage such, for instance, as allyl or crotyl.Furthermore, there are appropriate as R benzyl, ei-phenylethyl orpphenylethyl.

Within the scope of the invention there are particularly preferredcompounds containing as R a cycloaliphatic hydrocarbon radical which maybe substituted by alkyl orlinked to the nitrogen atom by means ofalkylene. Said radicals comprise, for instance, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, methyl cyclopentyl, methylcyclohexyl,ethyl-cyclohexyl, propyl-, and isopropylcyclohexyl. The alkyl groups canbe present in the cyclohexyl ring preferably in 4-position to thesulfonyl-urea substituent and may take there the cisas well as thetrans-position. Furthermore, there are mentioned:Endomethylene-cyclohexyl (2,2,--bicycloheptyl), endoethylene-cyclohexyl(2,2,2-bicyc1ooctyl), endomethylencyclohexenyl,endoethylenecyclohexenyl, endomethylenecycloherenylmethyl orendoethylene-cyclohexenylmethyl, endomethylene cyclohexylmethyl,endoethylene cyclohexylmethyl.

The grouping means for example, indolino, tetrahydro quinolino,furthermore groupings of the following formulae CH3 (.hHs C2 11 EH Grcarnal CH: 7 7 CH3 7 CH3 C1 I 3? @a 0H3 on, CHa

. (l1 CzHO Qt @a- I CH3 C 3 3 @e CH 1 on, on,

C 2H5 CH3O Cl (i) OH;

02115 2 a aH1 CH3- XII- C3H7 (i) Y may represent, for example, asaturated hydrocarbon radical of 1-3 carbon atoms in straight chain orbranched, such as:

The mentioned benzenesulfonyl-ureas may be prepared according to variousmethods which are generally used for the preparation of compounds ofthis kind. Thus amines of the formula RNI-I or, if desired their saltscan be reacted with benzenesulfonyl isocyanates, benzenesulfonylcarbamic acid esters, benzenesulfonyl thiolcarbarnic acid esters,benzenesulfonyl-ureas, benzefiesulfonyl-semicarbazides orbenzenesulfonyl-semicarbazones which are substituted by the groupNCONH-Y-- or benzenesulfonamides substituted by the group N-CONH--Y ortheir salts can be reacted with R-substituted isocyanates, carbamic acidesters, thiolcarbamic acid esters, carbamic acid halides or ureas orcorresponding benzenesulfonyl-ureas containing the molecule'unsaturatedcompounds can be hydrogenated and the products obin fluence the natureof the final product and it may theretained can be treated with alkalineagents if salt formation the benzenesulfonyl thiolcarba-mic' acid estersmay contai'n'in the alcghol co'mponent an alkyl radical or an arylradical or also a heterocyclic radical. Since this radical is split oflfin the reaction, its chemical constitution does not fore be variedwithin wide limits.

The same applies to the R-substituted carbamic acid esters or thecorresponding monothiol-carba-mic acid esters.

As carbaimic acid halides, the chlorides are particularly suitable.

Ihe benzenesulfonyl-ureas to be used as starting substances in theprocess of the present invention may be unsubstituted at the side of theurea molecule opposite to the "sulfonyl group or may be monoor, inparticular, di-substituted. Since these substituents are split oif inthe reaction with amines, their nature may be varied within Wide limits.In addition to benzenesulfonylureas carrying alkyl-, aryl-, acylorheterocyclic substituents, there may also be usedbis-(benzene-sulfonyl):ureas which may carry, at one of the nitrogenatoms, an. additional sub;- stituent, for example, methyl. For example,bis- (be'nz'enesulfonyl)-ureas or also N-benzenesulfonylN-acyl-ureas maybe treated with amines of the -formula Rl-NH and the salts obtained maybe heated to elevated temperatures, in particular, those above C.

Furthermore, it is' possible to start from ureas of the formula HiN-CO--NHR or from ureas which may carry, at the free nitrogen atom, oneor preferably two substitutents, and to react these with benzenesulfonamides carrying in 4-position the substituent As such startingcompounds, there may be mentioned for example the correspondingN-acetyl-, N-nitro-, N'- cyclohexyl-, EN'- (4-methy1-cyclohexyl)-,N',-N'-diphenyl- (wherein the two phenyl radicals may also carrysubstituents or may be linked to each other directly. or over a bridgemember such .as -CH --NH, 0 or S-) N '-methyl-N' -phenyl-,N,=N-dicyclohexyl-ureas as well as R-substituted carba-moyl-imidazols or-triazols.

As regards the reaction conditions, the forms ofrealizing the processesmay in general vary within wide limits and adapted to each individualcase. For example, the re action using solvents may be carried out atroom temperature or at an elevated temperature.

The benzene'sulfonyl-urea-derivatives, obtainable according to thepresent invention are valuable new remedies which are distinguished by astrong and long lasting blood sugar lowering action. The blood sugarlowering action can be determined for example at rabbits by feeding themthe products of the present invention in a dose of 10milligrams/kilograms, and measuring over aprolonged period of time,according to the known method of Hagedorn-Jensen or with anautoanalyzer, the blood sugar level. Thus, it was found, that.N-[4-(B-indolinocarbonamido-ethyl)-benzenesulfonyl] N (4methylcyclohexy1)-urea in a rabbit provokes a lowering of the bloodsugar of 32%, which after 24 hours still amounts to 29% and after 48hours still 13%. The N-[4-(/3-indolinocarbonamidoethyl)-benzenesulfonyl]-N' cyclohexylurea causes under given test conditions even a lowering ofthe blood sugar of 38% which, after 24 hours still amounts to 20%.? v

Furthermore, it has been found, that N-[4-(p- N- methyl-N-phenyl ureido-ethyl) benzenesulfonyl]-=N'- (4-methyl-cyclohexyl)urea in a rabbitprovokes after 3 hours a lowering of the blood sugar of 30%, which after24 hours still amounts to 49%. The N-[4-(B- N-4-methyl pheny1 l Nmethyl-ureido -ethyl) benzenesulfonyl]- N'-(4-methyl-cyclohexyl)-urea'causes after 16 hours under given test conditions a lowering of theblood sugar of 32%, which after 24 hours still amounts to 27% and after48 hours still 25%. The 'N -['4-(B- 2-chlorphenyl- .N-methyl-ureidoethyl)=benzensulfonyl] N cyclohexyl-urea likewise causes after 3 hours alowering of the blood sugar of 30% which after 24 hours still amounts to39%.

iCorersponding values have been found with other compounds of this classas shown by the following table:

Blood sugar lowering in rabbits after oral application Compound: ofmg/kg. (percent) N-[4 (B indolinocarbamidoethyl)-benzenesulfonyl]-N'-(4-methyl-cyclohexyl)-urea N-[4 (B1N 4 Methylphenyl N methylnreido -ethyl) benzenesulfonyl] N (4-methyl-cyclohexyl)-urea 2O N-[4 (B- N 3 Methylphenyl N methylureido-ethyl) benzenesulfonyl] iN' (4- methyl-cyclohexyl)-urea 2 6 lN-[4 (,B-'N 4 Methoxyphenyl N methylureido -ethyl)-benzenesu1fonyl] Ncyclohexyl-urea N-[4 (B N 3 TrifluoromethylphenyLN- methyl-ureido-ethyl) benzenesulfonyH-N- i(4-methylcyclohexyl)-urea 31 N- [4 (fl- N 3Methoxyphenyl N methylureido -ethyl) benzenesulfonyH I (4-unethylcyclohexyl -urea 'N-[4 (fl 2 Chlorophenyl N methylureido-ethyl)-benzenesulfonyl] N cyclohexyl-urea In contrast to this, theN-(4-methyl-benzenesulfonyl)- N'-butyl-urea which has been known asantidiabetic for oral administration when used in doses of less than 25milligrams/ kilogram remains without effect.

The benzenesulfonyl-ureas described are preferably used for themanufacture of orally applicable preparations for the lowering of theblood sugar level in the treatment of diabetes mellitus and may be usedas such or in the tform of their physiologically tolerable salts or inthe presence of substances which cause such salt formation. For theformation of salts, there may be used alkaline agents, such, forexample, as alkali metal hydroxides or alkaline earth metal hydroxides,alkali metal or alkaline earth metal, carbonates or bicarbonates,furthermore, ammonia or physiologically compatible organic nitrogenbases such as ethanolamine, diand triethanolamine, said alkaline agentsand bases being commonly used in the pharmaceutical industry to formphysiologically tolerable salts.

The pharmaceutical preparations are preferably in the form of tabletscontaining, in addition to the compounds of the invention, the usualadjuvants and carriers such as talc, starch, lactose, tragacanth ormagnesium stearate.

A pharmaceutical preparation containing one of the aforesaidbenzenesulfonyl-urea as active substance, for example, a tablet or apowder, with or Without the aforesaid carriers is advantageously broughtinto a suitable unit dosage form. The dose chosen should comply with theactivity of the benzenesulfonyl-urea used and the desired effect.Advantageously, the dosage per unit amounts to about 0.5 to 100milligrams, preferably 2 to 10 milligrams, but considerably higher orlower dosage units may also be used, which, if desired, are divided ormultiplied prior to their administration.

The following examples serve to illustrate the invention, but they arenot intended to limit it thereto.

EXAMPLE 1 N- [4-(fl-indolino-carbamidoethyl)-benzenesulfony1]-N'-cyclohexylurea 17.2 g. 4 (B indolinocarbamidoethyl) benzenesulfonamide(melting point 189191 C., prepared from 4 (,8 aminoethyl)benzenesulfonamide and indolinocarboxylic acid chloride) are suspendedin 200 ml. of acetone and dissolved in water with a solution of 2 g. ofsodium hydroxide. To this solution 6.5 g. cyclohexylisocyanate are addeddropwise while stirring at room temperature and stirring is continuedfor 2 hours. The mixture is then diluted with water, filtered, and thefiltrate is acidified with dilute hydrochloric acid. The precipitating N[4 (fi indolino carbamidoethyl) benzenesulfonyl]-N'-cyclohexyl-urea isreprecipitated from 1% of ammonia and recrystallized from water/ethanol.Melting point ZOO-202 C. In analogous manner there is obtained:

N-[4-(fl-indolino-carmabidoethyl)-benzenesulfonyl]-N'-(4-methylcyclohexyl)-urea, melting point l84l86 C.,

N- [4- ,B-indolino-carbamidoethyl )-benzenesulfonyl] (N'- butyl-urea,melting point 193195 C.,

N- [4 (B-indolino-carbamidoethyl -benzenesulfonyl] -N'-(4-ethylcyclohexyl)-urea, melting point 179l81 C.,

N- [4- (,B-indolino-carbamidoethyl -benzenesulfonyl] -N'-(2,5-endomethylene-cyclohexylmethyl)-urea, melting point 174176 C.

Furthermore it has been prepared in analogous manner:

N [4 ('y indolinocarbonamidopropyl) benzenesulfonyl]-N-cyclohexylurea,melting point C. (from methanol (water) from4-('y-indolinocarbonamidopropyl)-benzenesulfonamide (melting point 161C.),

N [4 (B indolinocarbonamidopropyl) benzenesulfonyl]-N'-cyclohexylurea,melting point 174 C. (from methanol/water), from 4 (Bindolinocarbonamidopropyl)-benzenesulfonamide (melting point 171 C.),

N [4 8 1,2,3,4 tetrahydro quinolino carbamido ethyl) benzenesulfonyl] Ncyclohexylurea, melting point 184-186 C. from the 4-([3- 1,2, 3,4tetrahydro quinolino carbamido ethyl)- benzene-sulfonamide, meltingpoint 138-139 C.,

N- [4- 5- 1 ,2,3,4-tetrahydro-quinolino-carbamidoethyl)-benzene-sulfonyl]-N-butyl-urea, melting point 135-137 C.,

N- [4- B- 1 ,2,3,4-tetrahydro-kuinolino-carbamido ethyl-benzenesulfonyl] -N'- (4-methyl-cyclohexyl urea, melting point 153l55C.,

N- [4- [3- N-benzyl-N-methyl-ureido -ethyl) -b enzenesulfonyl]-N'-propylurea, melting point 142l44 C.,

N- [4- (13- N-benzyl-N-methyl-ureido -ethyl-benzenesulfonyl]-N-hexyl-urea, melting point 98-101 C.,

N- [4- 3- N-benzyl-N-methyl-ureido -ethyl)-benzenesulfonyl]-N'-benzyl-urea, melting point 157l59 C.,

N- [4- (B- N-benzyl-N-methyl-ureido -ethyl-benzenesulfonyl]-N'-cyclohexylmethyl)-urea, melting point 167-169 C.,

N-[4-(B- N-benzyl-N-methyl ureido-ethyl)-benzenesulfonyl]-N-(A3-cyclohexenylmethyl)-urea, melting point-l62 C.,

N- [4- (/3- N-4-methoxyphenyl-N-methyl-ureido -ethyl) benzenesulfonyl]-N'- (4-isopropyl-cyclohexyl -urea, melting point 206208 C.,

N- [4- (fl- N-4-ethoxy-phenyl-N-methy1-ureido -ethyl benzene sulfonyl]-N- (4-tert.-butyl-cyclohexyl) urea, melting point 154l56 C.,

N- [4- ,8- N-3-methoxyphenyl-N-methyl-ureido -ethyl)benzenesulfonyl]-N-(4-methyl-A3-cyclohexenyl)-urea, melting point 130132C.,

N- [4- (;3- N-4-chlorophenyl-N-methyl-ureido -ethyl) benzenesulfonyl]-N- (2,5 -endomethylene-A3-cyclohexenyl)-urea, melting point l99-201 C.,

N- [4- 8- N-4-methyl-phenyl-N-methyl-ureido -ethyl) benzenesulfonyl] -N-(p-phenylethyl)-urea, melting point -172 C.,

N- [4- {i- N-4-methylphenyl-N-methyl-ureido -ethy1)-benzenesulfonyl]-N-cyclooctyl-urea, melting point 134-137 C.,

N- [4- fl- N-4-methylphenyl-N-methyl-ureido -ethyl)benzenesulfonyl]-N'-allyl-urea, melting point 178-180 C.,

N [4- ,8- N-4-methylphenyl-N-methyl-ureido -ethyl) benzenesulfonyl] -N-3-methyl-cyclopentyl) urea, melting point 153155 C.,

benzene-sulfonamide, metlingpoint 177-181 C.: N- [4- (13-N-4-bromopenylN-methyl-ureido -ethyl) benzene-sulfonyl]-N'-cycloheXyl-urea, melting point 173-175" C. I N-[4-(5-N-4-bromopenyl-N-methyl-ureido -etl1yl)- benzene-sulfonyl] -N'-(4-methyl-cyclohexyl -urea, melting point 189-191 C. N- [4- fl-N-4-bromopenyl-N-methyl-ureido -ethyl benzene-sulfonyl]-N-isobutyl-urea,melting point 1 56-158 C. from 4 (B N tert. butylphenyl-N-methyl-ureidoethyl)-benzenesulfonamide, melting point 164166 C.: N- [4-(,8- N-4-tert.butylphenyl-N-methyl-ureido ethyl -benzenesulfonyl] -N'-cyclohexyl-urea,melting point 191-l93 C.

from 4 (N methyl-N-phenyl-ureido-methyl)-benzene sulfonamide, meltingpoint 156-15 8 C.:

N- [4- N-methyl-N-phenyl-ureido-methyl-benzenesulfonyl]-N'-(4-methyl-cyclohexyl)-urea, melting point 172-174C.

from 4 (fl- N-4-iodo-phenyl-N-methyl-ureido -ethyl)- benzenesulfonamide,melting point l8l-183 C.:

N- [4- (,3- N-4-iodo-phenyl-N-methyl-ureido -ethyl benzene-sulfonyl]-N'- (4-methylcyclohexyl) -urea, melting point 194-196 C.

EXAMPLE 3 N- [4- N-4-chlorophenyl-N-methyl-ureido -ethyl)benzenesulfonyl] -N'-cyclohexyl-urea 10.6 g. 4 (B-N-4-chlorophenyl-N-methyl-ureido ethyl)-benzenesulfonyl-methyl urethane(melting point 188-190" 0, prepared from 4-(B- N-4-chlorophenyl-N-methyl-ureido -ethyl) benzenesulfonamide and chloroformic acidmethylester) are heated in an oil bath to 130 C. for 1 hour with 2.5 g.of cyclohexylamine. After cooling, the reaction product is precipitatedfrom 1% of ammonia and recrystallized from water/ethanol. The N-[4 (fl-N-4-chloro-phenyl-N-methyl-ureido -ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea melts at 173-175 C.

In analogous manner there is obtained: From We claim: 1. A compound ofthe formula (b) endoalkylene-cyclohexyl, endoalkylene cyclm 'hexenyl,endoalkylene-cyclohexylmethyl' or endoalkylene-cyclohexenylmethyl of 1-2endoalkyl- I ene carbon atoms, 1

(c) ,benzyL-phenylethyl,

(d) cyclohexyl methyl,

(e) lower alkyl cyclohexyl or dialkyl cyclohexyl,

methyl cyclopentyl,

(f) cycloalkyl of '5-8 carbon (g) cyclohexenyl, cyclohexenyl-methyl,

cyclohexenyl, or I p x (h) norticyclyl,

-(a) phenyl, trifluoromethyl phenyl, phenylsubstituted by one'to twosubstituents selected from the group consisting of halogen, lower al kyland lower alkoxy,. or a (b) benzyl, Yr

X is alkyl of 1 to 3 carbon atoms, and v I Y is alkylene of 1 to 3carbon atoms, or a salt thereof of a pharmaceutically acceptable base. v

2. Compound of'claim 1 wherein R is cyclohexyl'or 4- methyl cyclohexyl.I

3. Compound of claim 1 wherein Y is dimethylene.

4. Compound of claim 1' wherein X is methyl.

5. Compound of claim 1 wherein Riscycloheiky'lp-r 4- methyl-cyclohexyl,Y is' dimethylene and X is methyl.

6. N-[4-({3- N 4 methyl-pl'ienyl-N-methyl-ureido ethyl)-benzenesulfonyl] N- (4-methyl-cyclohexyl urea.

7. N-[4-(,Z- N 3 methylphenyl-N-niethyl-ureido ethyl) -benzenesulfonyl]-N'- 4-methyl-Cylohexyl urea.

8. N [4(- 8- N-4-methoxyphenyl-N-methyl-ureidoethyl)-benzenesulfonyl]-N-cyclohexyl-urea.

9. N- [4- (fi- N 3' trifluoromethyl-phenyl-N-methylureido-ethyl)-benzenesulfony1] (4-methyl-cyclohexyl)-urea. g I a j 10. N [4 (BN,-, 3.- 'methoxy-phenyl-N-methylureido -ethyl)-benzenesulfonyl] ..N 4(4-methyl-cyclohexyl)-urea. 1 i. A

12. N [4-(/3- N-2-chloro-phenyl-Nfmethyl-ureido ethyl)-benzenesulfonyl']N cyclohexyl-urea. 7

15. N [4-(,8- N-4-methylphenyl-N-methyl-ureido ethyl) -benzenesulfonyl]-N- 4-ethyl-cyc1ohexyl -urea.

16. N-[4-(fl-N-benzyl vN methyl-ureido-ethyD-benatoms the ring,

methylzenesulfonyl] -N -butyl-urea.

IRefererices Cited UNITED STATES PATENTS 3,448,149 6/1969' Aumulle'retal. 260553 LEON ZITVER, Primary Examiner G. A. SCHWARTZ, AssistantExaminer Us. 01. X.R';

UNITED STATES PATENT OFFICE I CERTIFIC @F CORRECTION Patent No. ,6 5, 56Dated Anril 11 N72 'Inventor(s) Helmnt It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

In the Heading:

After "F M5630" insert --and May 1M, 1966, Germany, F M9,2o7--.

Signed and sealed this 29th day of August 1972.

(SEAL) Attest:

EDWARQFLFLETQHERJR. ROBERT GOTTSGHALK Attestlng Officer Commissioner ofPatents FORM PO-105O (10-69) USCOMM-DC 60376-P69 U45. GOVERNMENTPRINTING OFFICE: I969 0-366-334

